title: Antiproliferative activity of colchicine analogues on MDR-positive and MDR-negative human cancer cell lines.
abstract: In this study the in vitro antitumor activity of a series of 20 colchicine analogues was tested and compared with colchicine and thiocolchicine on three different human cancer cell lines, two of which express the multidrug-resistance (MDR) phenotype. At concentrations from 1 nM to 100 microM, all compounds tested inhibited cancer cell proliferation. The IC50 values indicate that the three fluorinated analogues were the most active compounds, with a similar decreasing order of potency (IDN 5005 > IDN 5079 > IDN 5080) on the two MDR-expressing cell lines, whereas thiocolchicine was the most effective compound on the MDR-negative MDA-MB 231 cells. A strong correlation (r = 0.94; P = 0.004) was found between IC50 values obtained using the two MDR-positive cell lines. Conversely, IC50 values obtained in MDA-MB 231 cells did not show a significant correlation with MDR-positive cell lines, thereby suggesting some difference in the antiproliferative mechanism(s) of colchicine analogues. Cell cycle analysis of the most active analogues in breast cancer cells showed a relationship between cell cycle blocking activity and growth inhibition. The most active agents on the MDR-positive MCF7 ADRr cell line, after 24 h of culture, in terms of cell cycle blocking activity were the three fluorinated analogues. Interestingly, after 72 h, when the cell cycle block subsided, a consistent amount of DNA fragmentation was evident. The extent of cell cycle block, measured as the G2/G1 ratio, was significantly correlated with the apoptosis rate expressed as a percentage of DNA fragmentation on both cell lines, thereby suggesting that a large number of blocked cells underwent the apoptotic pathway.
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Vincenzo
authors.forename: G
authors.initials: G
authors.lastname: Scambia
authors.forename: C
authors.initials: C
authors.lastname: Ferlini
authors.forename: M
authors.initials: M
authors.lastname: Distefano
authors.forename: P
authors.initials: P
authors.lastname: Filippini
authors.forename: A
authors.initials: A
authors.lastname: Riva
authors.forename: E
authors.initials: E
authors.lastname: Bombardelli
authors.forename: D
authors.initials: D
authors.lastname: Pocar
authors.forename: M L
authors.initials: ML
authors.lastname: Gelmi
authors.forename: P
authors.initials: P
authors.lastname: Benedetti Panici
authors.forename: S
authors.initials: S
authors.lastname: Mancuso
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005461:Fluorine; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D005461:Fluorine; C014856:thiocholchicine; D003078:Colchicine